Leptin is a peptide hormone produced by adipose tissue and released in proportion to adipose mass. Leptin acts on the central nervous system to increase lipolysis and heat production through activation of the sympathetic nervous system. It is also a potent inhibitor of feeding behavior. A great deal is known about how leptin can invoke changes in transcription, resulting in the enhancement or suppression of the synthesis of peptide neurotransmitters that regulate feeding or metabolism. However, the mechanism by which leptin generates rapid changes in the excitability of neural pathways regulating autonomic and behavioral functions is less certain. A confounding factor in understanding rapid leptin signaling may be the high degree of cooperativity that exists between leptin transduction mechanisms and those of other agonists. This relationship may cause leptin action to be "gated" by parallel signals or, vice versa, leptin may "gate" the effectiveness of other agonists involved in autonomic or behavioral control. A synergistic relationship between leptin and other factors operating simultaneously may offer an intriguing explanation for the effects of temperature on the effectiveness of leptin and the effect of leptin to sensitize thermoregulatory mechanisms. The dorsal vagal complex [DVC] has receptor elements for leptin and receives thyrotropin releasing hormone [TRH]-ergic input from pathways known to command sympathetically-mediated increases in heat production. We propose that leptin and TRH action on DVC neurons is highly cooperative to the point that the presence of one agonist essentially "gates" the action of the other. Our preliminary results show that leptin applied alone to the dorsal medulla has no consistent effects on brown adipose tissue [BAT] temperature. TRH produces a small increase in BAT temperature. However, TRH and leptin applied to the dorsal medulla together produce an increase in BAT and core temperature 300 percent greater than leptin or TRH alone. This effect can be elicited in the acute decerebrate rat, suggesting that the effect is mediated entirely by the brainstem. Obesity is the consequence of a failure to balance feeding behavior with metabolic activity and has reached epidemic levels of incidence in virtually every modern society. Obesity exacerbates, or is a frank causative factor, in a number of chronic diseases. The accumulated financial burden associated with the effect of obesity to worsen the health of the population is over $240 billion per year. Unfortunately, evidence suggests that the incidence of obesity will increase over time. Clearly, a better understanding of the control of energy expenditure should be crucial to the control of obesity and is of critical scientific, clinical and societal importance. [unreadable] [unreadable] [unreadable]